Long-lived plasma cells (LLPC) sustain protective antibody production for a lifetime but the identity of the cellular source of human LLPC has eluded us for decades. In our lab, we have definitively linked the long-lived viral serum antibody source to a single cellular compartment within the human bone marrow (BM). The PC specificities concentrate in these unique long-lived viral specificities from exposures that occurred over 40-60 years ago. In this application, we will study the survival mechanisms of human BM LLPC by (1) understanding the ontogeny and survival of the short-lived PC and the LLPC, (2) testing the intrinsic molecular mechanisms of LLPC survival, and (3) defining the unique metabolic signatures of LLPC. The significance of this work is several-fold from understanding the means of generation to the mechanisms of maintenance (or survival) of human LLPC. It will provide insights to designing vaccine adjuvants, developing novel targets of pathogenic plasma cells in diseases such as autoimmunity, allergy, and transplantation (sparing protective LLPC), and offering novel diagnostic testing and drug pathways to treat multiple myeloma (oncology).